The field of medical radiography is well known. This is an extremely valuable tool for the early detection and diagnosis of various diseases of the human body. Different parts of the human body such as cavities and soft tissues of various organs and blood vessels evidence low X-ray radiation absorption. Thus, radiographing these body portions is difficult. To overcome this hurdle contrast agents which are opaque to X-ray radiation have been used.
Several inorganic materials have been used as contrast agents. Examples of these are bismuth subnitrate, bismuth subcarbonate, and barium sulfate, among others. U.S. Pat. No. 4,709,703 discloses a method of imaging an organ's tissue by perfusion with beads made of a metal or tungsten of 15-18 micron diameter.
Iodinated organic agents have also been used as contrast agents since the iodine atom is an effective X-ray absorber. Among these are iodinated oils, such as ethyl iodo-phenylundecylate, used for myelography, and water-soluble, iodinated organic compounds used for X-ray visualization of the gastrointestinal tract.
Water-soluble, iodinated organic compounds, however, can cause extremely severe side effects when used as a gastrointestinal contrast agent in dehydrated patients, especially infants. For this reason, these materials have become quite controversial and some radiologists no longer use such agents in the gastrointestinal tract (See, Radiographic Contrast Agents, Miller et al, p 169, University Park Press, Baltimore, Md. 21202 (1977)).
Water-insoluble, iodinated organic polymers have been used as contrast agents, as well. Such is the case of the product disclosed in British Patent Specification No. 1,400,985. This patent describes polymers containing iodine-substituted aromatic groups which are readily swellable in water to yield a gel. The iodine content of the polymers is between 20 and 35 wt %.
Biodegradable microspheres labeled with X-ray absorbent material have been used as contrast agents for the visualization of arterial circulation and the diagnosis of pulmonary embolism and other diseases in humans. U.S. Pat. No. 4,680,171 provides a method of visualizing the arterial circulation of a person by administering microspheres bearing an X-ray absorbent material, and subsequently X-raying the area of arterial circulation sought to be visualized. The medium utilized in this patent has microspheres of a 9-100 micron diameter. Examples of materials utilized in the prior art patent are albumin and starch.
U.S. Pat. No. 4,406,878 discloses a method for forming radiographic images of a body portion such as a human organ by introducing into the body portion a water-insoluble, non-water swellable iodinated polymer having an iodine content in excess of 35 wt % and then X-ray imaging the organ. The polymer is composed of a repeating organic unit forming the backbone chain of the polymer, and iodinated aromatic groups and hydrophilic groups which stick out from the backbone chain. The diameter of the polymer beads can be as high as 1,000 microns. The hydrophilic groups containing the iodine are attached to the backbone of the polymer by a linking group which may be an ester, ether, amide, thioester, carbonate, carbamate, sulfide and the like. The particle size of the beads may vary over a very broad range. The medium is therefore very inefficient and expensive to use since large amounts are required for a small proportion of the beads to reach a particular target tissue.
Iodinated compounds have been used in colloidal form in cholecystography. U.S. Pat. No. 1,858,142 discloses the production of a mono- and di-alkali metal salt of tetraiodophenolphthalein in colloidal form. U.S. Pat. No. 1,984,404 describes a similar composition comprising an alkali-metal salt of tetraiodophenolphthalein. The compound is provided for oral administration for the imaging of the hapatobiliary tract.
Water-soluble contrast agents have drawbacks such as their inherent hyperosmolality. Non-ionic agents were developed as a means to reduce hyperosmolality since they have about half the osmolality of their corresponding ionic monomers.
Particulate contrast agents were also developed because the particles make almost no contribution to the osmotic pressure of a medium. Accordingly, the use of particulate contrast agents affords the possibility of administering high iodine content materials which lack the fluid and ion shifts associated with water-soluble agents. An additional advantage of particulate contrast agents is the fact that their increased molecular size has no significant affect on the distribution volume thereof. That means that in fact there is more of the X-ray opaque component retained in the same volume. Moreover, the particulate contrast agents are initially retained exclusively within the vascular space. Only if they are of the correct size will they be phagocytized into the cellular space of an organ. Thus, for an initial period after their administration particulate contrast agents are useful for conducting blood flow and volume studies without using radioisotopes or any complex compartmental analysis necessary to account for any exodus of the particle into interstitial spaces.
Violante et al, Invest. Radiol. 15(6):S329-S334 (November-December 1980), Korman et al, Invest. Radiol. 19:133 (1984), and Sands et al (Invest. Radiol. 22(5):408-416 (May 1987) disclosed particulate contrast agents having diameters in the range of two microns and smaller. The agents are iodinated aromatic structures which are esterified and amidized with methanol and ethanol such as ethyl esters of iothalamic and iodipamic acid. These compounds are preincubated in human serum albumin to overcome in vivo particle aggregation and embolization. Similar compounds are used as antimicrobial agents in particulate form (see, U.S. Pat. No. 4,783,484).
However, the development of suitable particulate contrast agents has not been forthcoming because of the difficulties involved in their development. The size and shape of the particles must be such that they do not cause embolism in the capillaries, and in vivo particle aggregation must be avoided to prevent the occurrence of embolism. The uptake of the contrast agent by the desired tissue must be maximized while at the same time permitting its quick removal within a reasonable period of time. Moreover, any contrast agent to be useful and obtain approval for use in humans must have substantially reduced biological toxicity.
Accordingly, there still is a need for an improved X-ray imaging agent having the above characteristics.